To investigate the effect of mycophenolate mofetil (MMF) and rituximab (RTX) on pulmonary function test (PFT) results in a mixed cohort of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), longitudinally followed up for 1 year in a single academic center. Patients with CTD-ILD were identified in electronic medical records from 1 January 2009 to 30 April 2019. Prescribed MMF and RTX doses, dosage changes, and therapy plans were analyzed individually with improvement in PFT outcomes determined using multivariable linear regression models during 12-month follow-up. Forty-seven patients with CTD-ILD, treated with MMF, RTX, or both, were included. Patients on combined MMF and RTX had worse PFT outcomes at baseline compared with patients on monotherapy. Substantial improvement was observed among all PFT outcomes from baseline to 12 months, regardless of medication dosage or therapy plans. The diffusing capacity of the lungs for carbon monoxide (DLCO) worsened by an average of 7.21 mL/(min*mmHg) (95% CI, 4.08-10.33; < 0.001) among patients on RTX compared to combined therapy. Patients on higher doses of MMF at baseline experienced an average increase of 0.93 (95% CI, 0.04-1.82) units in DLCO from baseline to 6 months ( = 0.04) and a 2.79% (95% CI, 0.61-4.97%) increase in DLCO from 6 to 12 months ( = 0.02) within patients on concurrent RTX at 6-month follow-up. The treatment of CTD-ILD with MMF and/or RTX was associated with overall improvement in PFT outcomes. Combined therapy resulted in significant improvements in DLCO compared with monotherapy. Higher doses of MMF also provided greater improvements in DLCO.